Project Summary/Abstract Clinical manifestations of Alzheimer's disease (AD) such as memory loss and cognition impairment occur mostly in people aged 65 years. But the disease is believed to progresses silently for more than a decade before its clinical manifestations such that the disease process starts as early as in the middle of 40s. This preclinical phase of AD would provide a critical opportunity for effective therapeutic interventions. Thus, earlier identification of the individuals at the risk for AD is important for better healthy outcomes of these people and their caregivers. The goal of this project is to determine the ability of fractal regulation in physiological fluctuations to predict the risk of AD in middle to old aged people. Many physiological fluctuations including heart rate and motor activity fluctuations display fractal patterns, i.e., the patterns of fluctuations are very similar at different time scales. Numerous studies indicate that fractal regulation imparts considerable physiological advantage in terms of plasticity and adaptability, as exemplified by reduced fractal cardiac and motor activity regulations with aging and under pathological conditions, and most importantly, by the predictive value of reduced fractal cardiac regulation for decreased survival. PI's group is one of the first to show a mechanistic link between degraded fractal regulation and Alzheimer's disease (AD). They found that fractal motor activity regulation (FMAR) is degraded with aging and in AD, and that the degradation is strongly associated with cognitive decline. Based on these preliminary data, the proposal is designed to test whether FMAR alterations predict incident AD in middle to old aged people. To this end, PI and his team propose to study the existing database of UK Biobank (http://www.ukbiobank.ac.uk) in which ~500,000 participants aged between 40-69 years were recruited in 2006-2010 and agreed to have their health followed. The specific aims are 1) to determine the effects of age and genetic risk for AD on FMAR in middle-to-old aged adults; 2) to determine the associations of FMAR with cognition and incident AD in middle-to-old aged adults; and 3) to determine the effects of neuroanatomical changes on FMAR in middle-to-old aged adults. Addressing the aims will provide a first formal assessment of the alterations of fractal regulation from middle to old ages, the underlying neuroanatomical changes, and its ability to predict the risk of AD at early or preclinical stages. These results will lead to a much better understanding of the complex biology and physiology of healthy and pathologic aging in AD, which ought to provide useful guidance for improved diagnosis and treatment of AD or AD-related symptoms.